A Phase II Study of AT-101 to Overcome Bcl-2-Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer.

We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer.

Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (≤ 0. 2 ng/mL) after 7. 5 months (1. 5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients.

A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27. 6 ng/dL. Of the 55 patients, 72% had a Gleason score ≥ 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients.

The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination.

Clinical genitourinary cancer. 2015 Sep 21 [Epub ahead of print]

Mark N Stein, Maha Hussain, Walter M Stadler, Glenn Liu, Irina V Tereshchenko, Susan Goodin, Chandrika Jeyamohan, Howard L Kaufman, Janice Mehnert, Robert S DiPaola

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. , University of Michigan, Ann Arbor, MI. , University of Chicago, Chicago, IL. , UW Carbone Cancer Center, University of Wisconsin, Madison, WI. , Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. , Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. , Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. , Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. , Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. , Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. 

PubMed